Diabetes disturbs functional adaptation of the remote myocardium after ischemia/reperfusion

Funk, Florian; Kronenbitter, Annette; Isić, Małgorzata; Flocke, Vera; Gorreßen, Simone; Semmler, Dominik; Brinkmann, Maximilian; Beck, Katharina; Steinhoff, Oliver; Srivastava, Tanu; Barbosa, David; Voigt, Katharina; Wang, Luzhou; Bottermann, Katharina; Kötter, Sebastian; Grandoch, Maria; Flögel, Ulrich; Schmitt, Joachim P.

doi:10.1016/j.yjmcc.2022.09.002

Cited by 6 publications

(2 citation statements)

References 60 publications

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“…The regulation of SERCA 2a expression and/or activity controls the cellular contraction and relaxation of the heart, and alterations in this SR pump strongly affect cardiac function [15]. Several cardiomyopathies have often been associated with changes in SERCA 2a with reduced activity in HF, diabetes, or direct processes of I/R in the heart [25,33]. Recently, alterations in SERCA 2a function have been demonstrated in uraemic cardiomyopathy linked to CRS such as in CKD or AKI in experimental acute renal failure [18,26].…”

Section: Discussionmentioning

confidence: 99%

Targeting the TWEAK–Fn14 pathway prevents dysfunction in cardiac calcium handling after acute kidney injury

Poveda,

González‐Lafuente,

Vázquez‐Sánchez

et al. 2023

The Journal of Pathology

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Heart and kidney have a closely interrelated pathophysiology. Acute kidney injury (AKI) is associated with significantly increased rates of cardiovascular events, a relationship defined as cardiorenal syndrome type 3 (CRS3). The underlying mechanisms that trigger heart disease remain, however, unknown, particularly concerning the clinical impact of AKI on cardiac outcomes and overall mortality. Tumour necrosis factor‐like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor‐inducible 14 (Fn14) are independently involved in the pathogenesis of both heart and kidney failure, and recent studies have proposed TWEAK as a possible therapeutic target; however, its specific role in cardiac damage associated with CRS3 remains to be clarified. Firstly, we demonstrated in a retrospective longitudinal clinical study that soluble TWEAK plasma levels were a predictive biomarker of mortality in patients with AKI. Furthermore, the exogenous application of TWEAK to native ventricular cardiomyocytes induced relevant calcium (Ca2+) handling alterations. Next, we investigated the role of the TWEAK–Fn14 axis in cardiomyocyte function following renal ischaemia–reperfusion (I/R) injury in mice. We observed that TWEAK–Fn14 signalling was activated in the hearts of AKI mice. Mice also showed significantly altered intra‐cardiomyocyte Ca2+ handling and arrhythmogenic Ca2+ events through an impairment in sarcoplasmic reticulum Ca2+‐adenosine triphosphatase 2a pump (SERCA2a) and ryanodine receptor (RyR2) function. Administration of anti‐TWEAK antibody after reperfusion significantly improved alterations in Ca2+ cycling and arrhythmogenic events and prevented SERCA2a and RyR2 modifications. In conclusion, this study establishes the relevance of the TWEAK–Fn14 pathway in cardiac dysfunction linked to CRS3, both as a predictor of mortality in patients with AKI and as a Ca2+ mishandling inducer in cardiomyocytes, and highlights the cardioprotective benefits of TWEAK targeting in CRS3. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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Section: Discussionmentioning

confidence: 99%

Targeting the TWEAK–Fn14 pathway prevents dysfunction in cardiac calcium handling after acute kidney injury

Poveda,

González‐Lafuente,

Vázquez‐Sánchez

et al. 2023

The Journal of Pathology

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“…by posttranslational modification [ 6 , 3 ]. In mouse hearts it was shown that titin-mediated passive tension is significantly increased within hours after ischemia/reperfusion, whereas changes in collagen expression were observed only a few days after the ischemic event [ 5 , 4 ]. In contrast to these early adaptations, hearts from patients with end-stage ischemic heart failure showed increased collagen expression and microtubule-dependent changes to cardiomyocyte passive stiffness, whereas titin-based passive tension was reduced due to altered titin isoform composition [ 3 , 8 ].…”

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confidence: 99%

The origin of myocardial passive stiffness: more than the sum of its parts?

Krüger

2024

Pflugers Arch - Eur J Physiol

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Deficiency of the sphingosine-1-phosphate (S1P) transporter Mfsd2b protects the heart against hypertension-induced cardiac remodeling by suppressing the L-type-Ca2+ channel

Duse,

Schröder,

Srivastava

et al. 2024

Basic Res Cardiol

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The erythrocyte S1P transporter Mfsd2b is also expressed in the heart. We hypothesized that S1P transport by Mfsd2b is involved in cardiac function. Hypertension-induced cardiac remodeling was induced by 4-weeks Angiotensin II (AngII) administration and assessed by echocardiography. Ca2+ transients and sarcomere shortening were examined in adult cardiomyocytes (ACM) from Mfsd2b+/+ and Mfsd2b−/− mice. Tension and force development were measured in skinned cardiac fibers. Myocardial gene expression was determined by real-time PCR, Protein Phosphatase 2A (PP2A) by enzymatic assay, and S1P by LC/MS, respectively. Msfd2b was expressed in the murine and human heart, and its deficiency led to higher cardiac S1P. Mfsd2b−/− mice had regular basal cardiac function but were protected against AngII-induced deterioration of left-ventricular function as evidenced by ~ 30% better stroke volume and cardiac index, and preserved ejection fraction despite similar increases in blood pressure. Mfsd2b−/− ACM exhibited attenuated Ca2+ mobilization in response to isoprenaline whereas contractility was unchanged. Mfsd2b−/− ACM showed no changes in proteins responsible for Ca2+ homeostasis, and skinned cardiac fibers exhibited reduced passive tension generation with preserved contractility. Verapamil abolished the differences in Ca2+ mobilization between Mfsd2b+/+ and Mfsd2b−/− ACM suggesting that S1P inhibits L-type-Ca2+ channels (LTCC). In agreement, intracellular S1P activated the inhibitory LTCC phosphatase PP2A in ACM and PP2A activity was increased in Mfsd2b−/− hearts. We suggest that myocardial S1P protects from hypertension-induced left-ventricular remodeling by inhibiting LTCC through PP2A activation. Pharmacologic inhibition of Mfsd2b may thus offer a novel approach to heart failure.

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Diabetes disturbs functional adaptation of the remote myocardium after ischemia/reperfusion

Cited by 6 publications

References 60 publications

Targeting the TWEAK–Fn14 pathway prevents dysfunction in cardiac calcium handling after acute kidney injury

Targeting the TWEAK–Fn14 pathway prevents dysfunction in cardiac calcium handling after acute kidney injury

The origin of myocardial passive stiffness: more than the sum of its parts?

Deficiency of the sphingosine-1-phosphate (S1P) transporter Mfsd2b protects the heart against hypertension-induced cardiac remodeling by suppressing the L-type-Ca2+ channel

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